This invention relates to purine derivatives, to processes for their preparation, to compositions containing them and to their use.
More particularly, the present invention relates to the use of purine derivatives in the treatment of a variety of viral infections and immune or inflammatory disorders, including those in which the modulation, in particular agonism, of Toll-Like Receptors (TLRs) is implicated. Accordingly, the compounds of the invention are useful in the treatment of infectious disease such as Hepatitis (e.g. HCV, HBV), genetically related viral infections, inflammatory diseases such as asthma and arthritis, and cancer.
Toll-Like Receptors are primary transmembrane proteins characterized by an extracellular leucine-rich domain and a cytoplasmic tail that contains a conserved region named the Toll/IL-1 receptor (TIR) domain. They are expressed predominantly on immune cells (for example dendritic cells, T lymphocytes, macrophages, monocytes and natural killer cells), which serve as a key part of the innate immune system. They are a group of pattern recognition receptors which bind to pathogen-associated molecular patterns [for reviews, see for example, Ulevitch, R. J., Nature Reviews: Immunology, 4, 512-520, 2004 and Akira, S., Takeda, K., and Kaisho, T., Annual Rev. Immunol., 21, 335-376, 2003]. Their name derives from sequence homology to the Drosophila melanogaster gene Toll, which was found in fruit flies to play a key role in protecting the fly from fungal infections [Hoffmann, J. A., Nature, 426, 33-38, 2003]. There are 11 TLRs which have been identified in mammalian systems, and other non-mammalian TLRs have been found in other vertebrates. All TLRs appear to function as either a homodimer or heterodimer in the recognition of a specific, or set of specific, molecular determinants present on pathogenic organisms including bacterial cell-surface lipopolysaccharides, lipoproteins, bacterial flagellin, DNA from both bacteria and viruses and viral RNA. The cellular response to TLR activation involves activation of one or more transcription factors, leading to the production and secretion of cytokines and co-stimulatory molecules such as interferons, TNF-α, interleukins, MIP-1 and MCP-1 which contribute to the killing and clearance of the pathogenic invasion. By activating TLRs with small molecule agonists, it should be possible to induce or stimulate immune cells to mount an immune response.
Purine derivatives are disclosed in EP-A-0 882 727, EP-A-1 035 123, EP-A-1 043 021, EP-A-1 386 923 and WO 2004/029054. WO 2004/087049 and US 2005/054590 disclose modulators of TLR7.
There is a need for further modulators, especially agonists, of the activity of the TLR7 receptor, and preferably agonists which are more selective, have a more rapid onset of action, are more potent, are better absorbed, are more stable, are more resistant to metabolism, have a reduced ‘food effect’, have an improved safety profile or have other more desirable properties (e.g. with respect to solubility or hygroscopicity) than the compounds of the prior art.